TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

Abstract

We analyzed the functional outcome of the interaction between tumor-associated macrophages (TAMs) and natural killer (NK) cells. TAMs from ascites of ovarian cancer patients displayed an alternatively activated functional phenotype (M2) characterized by a remarkably high frequency and surface density of membrane-bound IL-18. Upon TLR engagement, TAMs acquired a classically activated functional phenotype (M1), released immunostimulatory cytokines (IL-12, soluble IL-18), and efficiently triggered the cytolytic activity of NK cells. TAMs also induced the release of IFN-γ from NK cells, which however was significantly lower compared with that induced by in vitro-polarized M2 cells. Most tumor-associated NK cells displayed a CD56 bright , CD16 neg or CD56 bright , CD16 dim phenotype, and very poor cytolytic activities, despite an increased expression of the activation marker CD69. They also showed downregulation of DNAM-1, 2B4, and NTB-A activating receptors, and an altered chemokine receptor repertoire. Importantly however, when appropriately stimulated, NK cells from the patients, including those cells isolated from ascites, efficiently killed autologous TAMs that expressed low, "nonprotective" levels of HLA class I molecules. Overall, our data show the existence of a complex tumor microenvironment in which poorly cytolytic/immature NK cells deal with immunosuppressive tumor-educated macrophages.Keywords: Human r Natural killer cells r Ovarian cancer r Tumor-associated macrophages Additional supporting information may be found in the online version of this article at the publisher's web-site [3][4][5][6]. Tumor and stromal cells produce chemokines such as CCL2 that recruit monocytes from peripheral blood. Once in tissue, the tumor microenvironment would prevent their differentiation into DCs while promoting differentiation into macrophages. Moreover, it would skew the macrophage polarization toward a proangiogenic/immunoregulatory M2-like phenotype with tumor-promoting properties. Notably, most studies have established a correlation between high numbers of tumorassociated macrophages (TAMs) within a tumor and poor prognosis [7][8][9]. Thus, an attractive novel clinical approach could be to identify factors able to revert TAMs into macrophages with M1 tumor-suppressive properties.Other innovative therapeutic protocols aim at increasing the function of immune effector cells with antitumor capabilities. Natural killer (NK) cells are appealing candidates for cancer immunotherapy [10,11] Results TAMs express high amounts of mIL-18TAMs were purified from ascitic fluids of patients affected by ovarian carcinoma (Table 1) and analyzed by flow cytometry for the expression of a large panel of cell surface markers ( Fig. 1 and Supporting Information Fig. 1). The results were compared with those obtained using in vitro IL-4-polarized M2 cells derived from peripheral blood monocytes of healthy donors. According to the gene expression profile analyses [19,20], the surface phenotype of TAMs closely resembled that of M2 cells (S...

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

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The Use of Toll-like Receptor 4 Agonist to Reshape the Immune Signature in Ovarian Cancer

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Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer

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